CCR5 & CXCR4 Antagonist & Agonist Binding Site Structure

CCR5

• 批准号: 7494756
• 负责人: EDWARD A DRATZ
• 金额: $ 1.17万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494756
• 关键词: Adverse effects; Affinity; Agonist; Amino Acid Sequence; Amino Acids; Anti-HIV Agents; Antibodies; Bacteriophages; Binding; Binding Sites; Bioinformatics; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cells; Chemokine (C-C Motif) Receptor 5; Complex; Cyanogen Bromide; Data; Development; Drug resistance; Epitope Mapping; Epitopes; HIV; HIV Envelope Protein gp120; HIV Infections; Helix (Snails); Immunologic Deficiency Syndromes; Infection; Inflammation; Label; Lead; Length; Maps; Mass Spectrum Analysis; Measures; Modeling; Molecular Conformation; Monoclonal Antibodies; Mutate; N-terminal; Opportunistic Infections; Peptide Mapping; Peptide Sequence Determination; Peptides; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Process; RANTES; Random Peptide Libraries; Rhodopsin; Role; Site; Site-Directed Mutagenesis; Staging; Stromal Cell-Derived Factor 1; Structure; Surface; T-Cell Development; Techniques; Testing; Toxic effect; Variant; Viral; Viral Physiology; Virus; Virus Diseases; Work; analog; chemokine receptor; crosslink; cytokine; design; drug development; ear helix; extracellular; imprint; improved; preference; receptor; receptor binding; receptor function; research study; small molecule; tool

Problems of drug resistance, latent viral reservoirs, and the toxic effects of current anti-HIV drugs call for the development of new anti-retrovirals with different modes of action. A promising approach for drug development is interference with the entry of HIV into cells. HIV entry is a complex process that requires binding of the HIV envelope protein gp120 to a cellular co-receptor (CCR5 or CXCR4). This proposal seeks to enhance understanding of the structure of CCR5 and CXCR4, including the amino acid residues that contribute to alternative modes of antagonist binding and contact residues involved in agonist activation. Virus isolates that require CCR5 for entry are the predominant infectious forms of HIV transmitted from one person to another. Virus strains that require CXCR4 for entry often emerge in the late stages of infection, are considered to be more pathogentic, and correlate with severe loss of CD4+ T lymphocytes and the development of opportunistic infections due to severe immunodeficiency. Several small-molecule antagonists for CCR5 or CXCR4 that block virus infection have been identified as promising drug leads by pharmaceutical companies, but their binding sites on the receptors and the mechanism of HIV blocking are poorly understood. This project will use high-affinity photoactive analogs of antagonist and agonist molecules to examine the interaction sites in CCR5 and CXCR4andwill investigate the roles of the residues at the crosslinking sites by site-specific mutagenesis. We will also investigate the changes in the conformation of CCR5 that result in activation or antagonism of HIV binding, by studying the interaction sites of monoclonal antibodies specific for the antagonist- or agonist-bound conformations of CCR5. The proposed studies will lead to a better understanding of the structure and function of CCR5 and CXCR4 and aim to provide information useful for the design of more potent drugs that inhibit HIV entry while minimizing side effects due to activating or blocking normal functions of CCR5 and CXCR4.

目前抗HIV药物的耐药性、潜在病毒库和毒性作用等问题需要 开发具有不同作用模式的新型抗逆转录病毒药物。一种有前途的药物治疗方法 发展是干扰艾滋病毒进入细胞。艾滋病毒进入是一个复杂的过程， HIV包膜蛋白gp120与细胞共受体（CCR5或CXCR4）的结合。该提案寻求 以增强对CCR5和CXCR4结构的理解，包括 有助于拮抗剂结合的替代模式和参与激动剂活化的接触残基。 需要CCR5进入的病毒分离物是由一种病毒传播的HIV的主要传染形式。 人对另一个人。需要CXCR4进入的病毒株通常出现在感染的晚期， 被认为更具致病性，并与CD4+ T淋巴细胞的严重损失和 由于严重免疫缺陷而发生机会性感染。几种小分子 阻断病毒感染的CCR5或CXCR4的拮抗剂已被鉴定为有前景的药物先导物， 但是它们在受体上的结合位点和HIV阻断的机制， 不太了解。这个项目将使用拮抗剂和激动剂分子的高亲和力光敏类似物 检查CCR5和CXCR4中的相互作用位点并将研究残留物在 通过位点特异性诱变的交联位点。我们还将研究构象的变化， 通过研究单克隆抗体的相互作用位点， 对CCR 5的拮抗剂或激动剂结合构象特异的抗体。拟议的研究将 从而更好地了解CCR5和CXCR4的结构和功能，旨在为 这些信息有助于设计更有效的药物，抑制艾滋病毒进入，同时最大限度地减少由于 激活或阻断CCR5和CXCR4的正常功能。